ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice.

ATP Binding Cassette Transporter, Subfamily B / genetics Animals Carbon Tetrachloride Chemical and Drug Induced Liver Injury / genetics Extracellular Matrix Proteins / deficiency Hepatic Stellate Cells / metabolism Hepatitis, Alcoholic / metabolism Hepatitis, Viral, Human / metabolism Humans Liver / metabolism Liver Cirrhosis, Alcoholic / metabolism Liver Cirrhosis, Experimental / genetics Male Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Signal Transduction Transforming Growth Factor beta / metabolism ATP-Binding Cassette Sub-Family B Member 4
Cirrhosis ECM Integrin Signaling Mouse Model

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
11 2019
Historique:
received: 29 10 2018
revised: 08 07 2019
accepted: 15 07 2019
pubmed: 31 7 2019
medline: 20 12 2019
entrez: 31 7 2019
Statut: ppublish

Résumé

Activation of TGFB (transforming growth factor β) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1 ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Sections du résumé

BACKGROUND & AIMS
Activation of TGFB (transforming growth factor β) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers.
METHODS
We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1
RESULTS
ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with αv integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl
CONCLUSIONS
ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Identifiants

DOI: 10.1053/j.gastro.2019.07.036 PMID: 31362006
pubmed: 31362006
pii: S0016-5085(19)41133-5
doi: 10.1053/j.gastro.2019.07.036
pii:
doi:

Substances chimiques

ATP Binding Cassette Transporter, Subfamily B 0
ECM1 protein, human 0
Ecm1 protein, mouse 0
Extracellular Matrix Proteins 0
Transforming Growth Factor beta 0
Carbon Tetrachloride CL2T97X0V0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1352-1367.e13

Informations de copyright

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

Auteurs

Weiguo Fan (W)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Tianhui Liu (T)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Wen Chen (W)

CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Seddik Hammad (S)

Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.

Thomas Longerich (T)

Sektion Translational Gastrointestinal Pathology, Institute of Pathology, Heidelberg University, Heidelberg, Germany.

Ingrid Hausser (I)

Sektion Translational Gastrointestinal Pathology, Institute of Pathology, Heidelberg University, Heidelberg, Germany.

Yadong Fu (Y)

Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Nan Li (N)

School of Life Science and Technology, Shanghai Tech University, Shanghai, China.

Yajing He (Y)

Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Cui Liu (C)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Yaguang Zhang (Y)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Qiaoshi Lian (Q)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Xinhao Zhao (X)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Chenghua Yan (C)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Li Li (L)

CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.

Chunyan Yi (C)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Zhiyang Ling (Z)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Liyan Ma (L)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Xinyan Zhao (X)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Hufeng Xu (H)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Ping Wang (P)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Min Cong (M)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Hong You (H)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

Zhihong Liu (Z)

Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Yan Wang (Y)

Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Jianfeng Chen (J)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Dangsheng Li (D)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Lijian Hui (L)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Steven Dooley (S)

Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: Steven.Dooley@medma.uni-heidelberg.de.

Jinlin Hou (J)

Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: jlhousmu@163.com.

Jidong Jia (J)

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China. Electronic address: jia_jd@ccmu.edu.cn.

Bing Sun (B)

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China. Electronic address: bsun@sibs.ac.cn.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Sous-famille B de transporteurs à cassette liant l'ATP › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Eucaryotes › Animaux › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures halogénés › Hydrocarbures chlorés › Tétrachloro-méthane › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Troubles dus à des produits chimiques › Intoxication › Lésions hépatiques dues aux substances › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Scléroprotéines › Protéines de la matrice extracellulaire › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Cellules › Cellules étoilées du foie › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Troubles dus à des produits chimiques › Troubles dus à l'abus d'alcool › Maladies alcooliques du foie › Hépatite alcoolique › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Hépatite › Hépatites virales humaines › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Système digestif › Foie › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Troubles dus à des produits chimiques › Troubles dus à l'abus d'alcool › Maladies alcooliques du foie › Cirrhose alcoolique › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Techniques d'investigation › Modèles animaux › Cirrhose expérimentale › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée BALB C › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › ECM1 Prevents Activation of Transforming...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › ECM1 Prevents Activation of Transforming...